The long term objective of this research program is to elucidate the mechanisms of carcinogenesis by nickel compounds. The specific aims of this proposal are: (a) to investigate the inhibitory effect of managanese upon the carcinogenicity of nickel subsulfide (Ni3S2); (b) to identify the metabolic basis for the pronounced differences which have been found between the carcinogenicities of Ni3S2 and nickel sulfide (NiS); and (c) to characterize and standardize an experimental system for induction of renal carcinomas in rats by intrarenal injection of Ni3S2. The methods will include: (a) carcinogenesis testing following administration of Ni3S2, NiS, Mn and other compounds to Fischer rats by intramuscular and/or intrarenal injection; (b) biochemical studies of the acute effects of intrarenal injection of NI3S2, including measurements of incorporation of C14 and H3 labelled precursors into DNA, RNA, and microsomal proteins; (c) histological and electron microscopic investigations of pathological lesions that are associated with induction of renal carcinomas by Ni3S2; and (d) compartmental analysis of Ni63 and S35 kinetics in order to identify differences in the metabolism of radiolabelled Ni3S2 and NiS in rats. This study is designed to provide fundamental knowledge of metal carcinogenesis, and also to furnish information which will have practical applications to assessing human hazards of carcinogenesis from nickel compounds, with particular relevance to energy research, industrial toxicology and environmental pollution.